Haematophagous insects and certain other blood-feeding arthropods are ubiquitous ectoparasites of animals, including humans. In so doing, blood-feeding ectoparasitic arthropods constitute a major source of annoyance to humans and other animals, and are vectors of many microbial diseases, as well as those caused by viruses and virus-like disease agents (Harwood and James 1979).
Blood-feeding arthropods that annoy man and animals through their biting and feeding activity, and often vector disease-causing pathogens, comprise members of numerous insect taxa, including, but not limited to: flies in the Families Culicidae, Tabanidae, Psychodidae, Simuliidae, Muscidae and Ceratopgonidae (Order Diptera), bugs in the Families Cimicidae and Reduviidae (Order Hemiptera), lice in the Orders Mallophaga and Anoplura, and fleas in the Order Siphonaptera, as well as non-insectan arthropods, particularly ticks and mites in the Order Acari (also known as Acarina).
An example of a significant annoyance to humans and a major vector of disease-causing pathogens is the yellow fever mosquito, Aedes aegypti (Diptera: Culicidae), an exceptionally resilient blood-feeding species that breeds in any small container of water (Malavige et al. 2004). Adults are highly domesticated, typically resting indoors in dwellings, thus optimizing their opportunity to feed and vector pathogens that cause diseases such as yellow fever and dengue fever (Mackenzie et al. 2004; Malavige et al. 2004; Hill et al. 2005). Annually, 7.2 million humans become infected with yellow fever, and >30,000 die from the disease. Moreover, 50-100 million humans are infected with dengue fever (500,000 with its henmorhagic form), resulting in approximately 24,000 deaths annually (Zanotto et al. 1996; Mairuhu et al. 2004). Other species of Aedes, as well as mosquitoes in other genera, particularly Anopheles and Culex, are also significant annoyance agents and vectors of disease-causing pathogens.
The most effective protection against mosquitoes and other ectoparasitic arthropods, is to repel them from, or deter their landing and feeding on, potential hosts. Until recently, the most efficacious known “repellent” was N,N-diethyl-m-toluamide (DEET) (Fradin and Day 2002). There are concerns associated with N,N-diethyl-m-toluamide. It is a solvent for some plastics, paints, varnishes and synthetic fabrics (Trigg 1996; Badolo et al. 2004; Miot et al. 2004). When used alone it may attract rather than repel A. aegypti. Finally, products exceeding 30% N,N-diethyl-m-toluamide are not recommended for protection of children (Pest Management Regulatory Agency 2002). Thus, there is a strong need for alternatives to N,N-diethyl-m-toluamide.
Research has led to several alternative repellents and deterrents to date (TABLE 1), some of them with efficacy equal to that of N,N-diethyl-m-toluamide (Barnard and Xue 2004). Many of these are natural compositions, and include essential oils from plants (cedar, rosemary, eucalyptus, andiroba, catnip, thyme, neem, clove, soybean) and grease or oils from animals. Active ingredients in some of these oils have been isolated and formulated in commercial products. OFF!® botanicals, for example, contain p-menthane-3,8-diol from lemon eucalyptus, Eucalyptus maculata citriodon (Beldock et al. 1997; Carroll and Loye 2006) as the active ingredient. Other new repellents for mosquitoes and other arthropods that are found in natural sources include: 2-undecanone (methyl nonyl ketone) from tomato plants (Roe 2002, 2004, 2007; Roe et al. 2006); tetrahydronootkatone (1,4,4a,5,6,7,8,10-octahydro-6-isopropyl-4,4a-dimethyl-2(1H)-naphthalenone) and 1,10-dihydronootkatone (1,4,4a,5,6,7,8,10-octahydro-6-isopropenyl-4,4a-dimethyl-2(1H)-naphthalenone) from yellow cedar (Zhu et al. 2005); and callicarpenal (13,14,15,16-tetranor-3-cleroden-12-al) and intermedeol [(4S,5S,7R,10S)-eudesm-11-en-4-ol] from American beautyberry (Cantrell et al. 2005, 2006; Carroll et al. 2007).
TABLE 1Names, ingredients, and formulations of 13 representative mosquitorepellents. Concentration of ingredients as stated on product label.Names and ingredientsNeem Aura: Aloe vera, extract of barberry, camomile, goldenseal, myrrh,neem, and thyme; oil of anise, cedary citronella, coconut, lavender,lemongrass, neem, orange, rhodiumwood. NeemAura Naturals, Inc.,Alachua, FLGonE!: Aloe vera, camphor, menthol, oils of eucalyptus, lavender,rosemary, sage, and soybean. Aubrey Organics, Tampa, FLSunSwat: oils of bay, cedarwood, citronella, goldenseal, juniper, lavender,lemon peel, patchouli, pennyroyal, tea tree, and vetivert. Kiss My FaceCorp., Gardiner, NYNatrapel: citronella (10%). Tender Corp., Littleton, NHBygone: oils of canola, eucalyptus, peppermint, rosemary, and sweetbirch.Lakon Herbals, Inc., Montpelier, VTBite Blocker: glycerin, lecithin, vanillin, oils of coconut, geranium, andsoybean (2%). Homs, LLC, Clayton, NCBioUD8: undecanone (7.75%). Homs, LLC, Clayton, NCSkinsations: N,N-diethyl-m-toluamide (7%). Spectrum Corp., St.Louis, MOOff!: N,N-diethyl-m-toluamide (15%). S. C. Johnson & Sons,Inc., Racine, WIAvon Skin-So-Soft Bug Guard plus IR3535: 3-(N-butyl-N-acetyl)-aminopropionic acid, ethyl ester (7.5%). Avon Products, Inc., New YorkAutan Active Insect Repellent: 1-(1-methyl-propoxycarbonyl)-2-(2-hydroxy-ethyl)-piperidine (Picaridin KBR-3023) (10%). Bayer Ltd.,Dublin, IrelandRepel: lemon eucalyptus insect repellent lotion. Oil of lemoneucalyptus (65% p-methane-3,8-diol [PMD]). Wisconsin Pharmacal Co.,Inc., Jackson, WIMosquitoSafe: geraniol 25%, mineral oil 74%, Aloe vera 1%. NaturaleLtd., Great Neck, NY
Many of the patented repellents and deterrents for arthropods are compositions. These are of two types: 1) compositions comprising a single active ingredient formulated with one or more inert ingredients that serve as a carrier or stabilizer, and 2) compositions of two or more active ingredients that provide an additive or synergistic effect on efficacy of the composition over that provided by any of the components alone. Compositions of the second type usually also have inert ingredients as formulants.
Examples of the first type of composition include: p-menthane-3,8-diol in ethylene/vinyl acetate co-polymer (Sikinami et al. 1991); N,N-diethyl-m-toluamide formulated in a liquefiable powder (Nichols 1993); garlic juice in filtered water (McKenzie 1995); carane-3,4-diol in a cellulose matrix (Ishiwateri 1999); and N,N-diethyl-n-toluamide formulated as an emulsion (Ross 2003).
Compounds used as additives with other repellents include, but are not limited to: vanillin, 1,8-cineole, linalool, citronellal, citronellol, camphor, menthone, isomenthone, menthol, borneol, isomenthol, α-terpineol, cis- and trans-piperitol, nerol, neral, cinnamaldehyde, cumin aldehyde, geraniol, geraniol, thymol, bornyl acetate, menthyl acetate, cumin alcohol, geranyl formate, geranyl acetate, caryophyllene, and cis-cinnamyl acetate. As indicated in some of the following examples, repellent additives are often combined with N,N-diethyl-m-toluamide to improve its efficacy.
Specific examples of the second type of composition include: 1,2,3,4-tetrahydro-β-naphthol and 2-phenyl cyclohexanol (Pijoan and Jachowski 1950); N,N-diethyl-m-toluamide and halobenzoylproprionate (1977, Dec. 20, U.S. Pat. No. 4,064,268); N,N-diethyl-m-toluamide, citral and citronella oil (Hautmaim 1979); oils of citronella, cedar, wintergreen and pennyroyal in an oleic acid carrier (Sherwood and Sherwood 1992); N,N-diethyl-m-toluamide and N-alkyl neotridecanamide (Polefka et al. 1997); p-menthane-3,8-diol, citronella, geraniol and α-terpineol (Beldock et al. 1997); geraniol, citronellol and nerol (Butler 2001); and N,N-diethyl-m-toluamide and dihydronepalactone (Hallahan 2007).
Vanillin has been shown to improve the repellence of N,N-diethyl-m-toluamide against black flies (Retnakaran 1984), and extracted oils of four species of plants (of 11 tested) against mosquitoes (Tuetun et al. 2005; Choochote et al. 2007). On the other hand, Fried et al. (2007) teach that “vanillin may be added as a stabilizer” in combination with a number of essential plant oils, but do not report any increase in repellence against flies and mosquitoes.
Garlic, Allium sativum, has well known antibacterial, antihelminthic and antitumor properties (Block 1992). It is also used with uncertain efficacy and understanding as an insect repellent. Bassett (1998) claims repellence of mosquitoes with a composition of garlic juice and hot pepper sauce, but does not reveal the contribution of each of these components. McKenzie (1995) describes a simple method of combining garlic juice and water to make a composition for repelling insects from fruit and vegetable plants. Arand and Arand (2002, 2003) improved on the methodology of McKenzie (1995), by developing a method of combining a measured amount of extract of a garlic puree with an inert carrier to form a composition of known concentration that is then added to a more conventional pesticide to improve its efficacy in a maimer that “is not totally understood at this time.” Similarly, Anderson and Brock (1998) claim that spraying dilute garlic juice on a grassy area can repel mosquitoes for many months, for “reasons not wholly understood”. Arand and Arand (2002, 2003) report improvements in the preparation of garlic extract and the use of said extract in composition with known insecticides.
Consumption of garlic as a means of repelling mosquitoes is widely practiced (Moore et al. 2006), but with no proven efficacy (Rajan et al. 2005). Weisler (1989) reports that administration of a 1:20 composition of aneurine (Vitamin B1) and garlic oil in the diet of domesticated animals can protect them from ingestion by fleas and ticks. However, in a test with flea-infested dogs, neither component was effective alone, and Weisler (1989) did not disclose whether either aneurine or some component of garlic oil actually was present in the skin of the test dogs. Therefore, the actual role of both components is uncertain. Moreover, Weisler (1989) erroneously teaches that allyl sulfide is the same as garlic oil, when in fact garlic oil is a complex mixture of many compounds (see FIG. 1).
Topical application of pure garlic oil can also be used to repel mosquitoes. Such an application provided 70 minutes of protection against A. aegypti (Trongtokit et al. 2005). Similarly, garlic oil (1%) formulated in petroleum jelly and beeswax provided 8 hours of protection against Culex fatigans (Bhuyan et al. 1974).
No systematic experimental study has been done to determine the identity of potentially bio-active compounds in garlic and garlic oil. Therefore, the ingredients therein that express repellence and deterrence to blood-feeding insects and other blood-feeding arthropods are unknown.